13-32319232-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4BP6_Very_Strong

The NM_000059.4(BRCA2):c.223G>C(p.Ala75Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000335 in 1,613,598 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A75T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:25O:1

Conservation

PhyloP100: 5.00

Publications

42 publications found

Variant links:

COSMIC-nc: COSV99061709

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
pancreatic cancer, susceptibility to, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 41 uncertain in NM_000059.4

BP4

Computational evidence support a benign effect (MetaRNN=0.29016286).

BP6

Variant 13-32319232-G-C is Benign according to our data. Variant chr13-32319232-G-C is described in ClinVar as Benign. ClinVar VariationId is 51258.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.223G>C	p.Ala75Pro	missense_variant	Exon 3 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.223G>C	p.Ala75Pro	missense_variant	Exon 3 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000614259.2 link	n.223G>C		non_coding_transcript_exon_variant	Exon 2 of 26	2		ENSP00000506251.1
BRCA2	ENST00000530893.7 link	c.-147G>C		5_prime_UTR_variant	Exon 3 of 27	1		ENSP00000499438.2

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000259

AC:

AN:

251354

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000336

AC:

491

AN:

1461362

Hom.:

Cov.:

AF XY:

0.000327

AC XY:

238

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33470

American (AMR)

AF:

0.000626

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000401

AC:

446

AN:

1111576

Other (OTH)

AF:

0.000248

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000328

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41534

American (AMR)

AF:

0.000720

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68016

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000357

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:25Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:7Other:1

Mar 17, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BRCA2 p.Ala75Pro variant was identified in 6 of 9140 proband chromosomes (frequency: 0.001) from individuals with breast, ovarian, or prostate cancer (Borg 2010, de SanJose 2003, Kote-Jarai 2011, Soegaard 2008); however, control chromosomes were not analyzed from these studies, thus the prevalence of the variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs28897701) â€šÃ„ÃºWith non-pathogenic alleleâ€šÃ„Ã¹, HGMD, UMD (91X as a neutral variant), and the BIC database (51X with unknown clinical importance). The variant was listed in the NHLBI Exome Sequencing Project in 4 of 8600 European American alleles (frequency: 0.0005), increasing the likelihood that it may be a low frequency benign variant in certain populations. This residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. One functional study found no effect of the variant on mRNA transcript levels as compared to wildtype, and two multifactorial based models predict the variant to be non-pathogenic or of no clinical significance (Muller 2011, Capanu 2011, Lindor 2012). In addition, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple publications classify as VUS/notpathogenic; ExAC: 17/66638 European chromosomes

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:5

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 02, 2020

BRCAlab, Lund University

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000000928

not provided

Benign:4

Oct 18, 2018

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BRCA2: BP4, BS1, BS2

Nov 30, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24055113, 18559594, 25985138, 21952622, 21520273, 21990134, 22505045, 24323938, 12845657, 27616075, 24728327, 21939546, 20104584, 28678401, 17924331, 28680148, 15307796, 25637381, 27741520, 32123317)

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:4

Mar 30, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Nov 19, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Feb 19, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 12, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary breast ovarian cancer syndrome

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

Breast and/or ovarian cancer

Benign:1

Dec 27, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breast neoplasm

Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

Familial cancer of breast

Benign:1

Feb 23, 2017

Baylor Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.0

.;.

M_CAP

Benign

0.073

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;.

PhyloP100

5.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.053

T;T

Vest4

0.63

ClinPred

0.088

GERP RS

5.6

gMVP

0.57

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over